PCSK9 Inhibitors: A New Option in Cholesterol Treatment
Medically reviewed by Leigh Ann Anderson, PharmD. Last updated on Dec 10, 2019.
Flashback: A Review of Statins
By now you've heard of statins, also known as HMG-CoA reductase inhibitors. Statins are the cornerstone of treatment to help regulate cholesterol production. Available since the late 1980's, statins include well-known blockbusters like:
Statins work so well because they block an enzyme involved in the production of cholesterol in the liver and boost the number of low density lipoprotein (LDL) receptors to help clear the body of LDL ("bad cholesterol").
However, as researchers have reported, a new class of drugs may change the face of lowering LDL cholesterol, especailly for hard-to-treat patients that don't fully respond to statins. These drugs are known as the Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors.
What Are PCSK9 Inhibitors?
The PCSK9 inhibitors are a class of injectable drugs approved in 2015 that have been shown to dramatically lower LDL cholesterol levels -- by up to 60% in some reports -- when combined with a statin. They may also be used alone as an adjunct to diet (without a statin) in certain cases.
PCSK9 inhibitors are monoclonal antibodies (MABs), a type of biologic drug.
- They bind to and inactivate an enzyme in the liver called proprotein convertase subtilisin kexin 9 (PCSK9).
- It's important to block PCSK9 because it inactivates the needed receptors on the liver cell surface that transport LDL into the liver for metabolism (break down).
- Without these receptors, more LDL ("bad" cholesterol) remains in the blood.
So, by inactivating PCSK9, more receptors are available to capture LDL for break down and removal from the blood. And, as we know, lower LDL is better for the heart, and can protect against heart disease, heart attacks and stroke.
Who Needs a PCSK9 Inhibitor?
According to the Centers for Disease Control and Prevention (CDC), about one-third, or 71 million American adults have high levels of low-density lipoprotein (LDL), or “bad,” cholesterol.
- However, only 1 out of every 3 adults with high LDL is receiving adequate treatment.
- Less than half of adults with high LDL cholesterol get treatment.
- In addition, there are about 11 million people who cannot reach their LDL cholesterol goals, even though they have been on a first-line treatment like statins.
In fact, about 1 in 5 patients on statins cannot lower their cholesterol adequately at all; some due to serious genetic defects. In addition, some patients stop their statin treatment due to side effects, like intolerable or dangerous muscle aches, muscle or liver damage, or the development of type 2 diabetes.
PCSK9 inhibitors are used:
- in combination with maximally tolerated doses of statins like atorvasatin or rosuvastatin to further lower the hardest-to-treat elevated cholesterol levels for adult patients with heterozygous familial hypercholesterolemia (HeFH) or heart disease, who require additional lowering of LDL-cholesterol.
- as an adjunct to diet, alone or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for the treatment of adults with primary hyperlipidemia to reduce low-density lipoprotein cholesterol (LDL-C).
Clinical Studies for PCSK9 Inhibitors
Several PCSK9 studies published in the New England Journal of Medicine (NEJM) show that two agents, evolocumab (Repatha) or alirocumab (Praluent), when combined with statins, lower cholesterol better than using just the statin alone.
After one year, those patients who were taking both the PCSK9 inhibitor and the statin together had LDL levels that were at least 60 percent lower than the group taking only statins. LDL levels dropped dramatically.
Larger studies have also looked at PCSK9 inhibitor ability to lower outcomes like heart attack, stroke, or death, and results suggest cardiovascular events could be significantly lowered by using these medications.
PCSK9 Inhibitors: Administration and Costs
PCSK9 inhibitors are given by subcutaneous (under the skin) injection, via self-administration with a pen device, one or two times per month. In general, PCSK9 inhibitors have been well-tolerated, but the common cold, itching, flu, injection site reactions, and serious allergic reactions have been reported.
Injection site reactions, such as redness, itching or pain are the most common reaction but infrequently lead to discontinuation of treatment.
Costs: These drugs are monoclonal antibodies (MABs), large molecule drugs that are usually very expensive. The good news is that these drugs have recently come down in price; however, the prices in general are still very high for what most people can afford without insurance.
- The lowest price for Praluent runs about $5,000 per year (coupon cash price without insurance) in the US, but this is variable based on the pharmacy you go to and your dose.
- Repatha from Amgen lowered the price in October 2018. Using a coupon, the average price also runs about $5,400 per year. but is variable.
- Individual pricing for patients can be affected by formulary coverage of the drug, copays, rebates, coupons, patient assistance, pharmacy, drug dose, and insurance type (government or private). Prices can climb as high as $8,000 per year.
- Contact your insurance company or pharmacist to learn more about how pricing might affect you for a PCSK9 inhibitor. Ask if one is preferred over the over on their formulary.
Praluent (alirocumab) by Sanofi / Regeneron
- as an adjunct to diet, alone or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for the treatment of adults with primary hyperlipidemia (including heterozygous familial hypercholesterolemia, HeFH) to reduce low-density lipoprotein cholesterol (LDL-C).
- to reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease.
Clinical studies include ODYSSEY and ODYSSEY OUTCOMES.
- ODYSSEY was an 18-month, phase 3 trial of 2,341 high-risk patients with high cholesterol on statin therapy. LDL was reduced over 60% after 24 weeks, and remained low over 78 weeks.
- The incidence of pre-specified cardiac adverse events like heart attack or stroke were lower in the alirocumab group (1.7%) compared to placebo (3.3%). Full cardiovascular outcomes (the effect of Praluent on heart problems such as heart attacks, stroke, or death) have now been reported and updated in the label.
ODYSSEY OUTCOMES: Praluent Cardiovascular Outcomes
In April 2019 the FDA approved labeling for Praluent based on data from the ODYSSEY OUTCOMES trial, which was published in the New England Journal of Medicine in November 2018. Praluent is now approved to reduce the risk of myocardial infarction (heart attack), stroke, and unstable angina (chest discomfort caused by poor blood flow to the heart) requiring hospitalization in adults with established cardiovascular disease.
Results from the ODYSSEY OUTCOMES trial (Schwartz and colleagues) with 18,924 patients showed that among patients with a history of acute coronary syndrome 1 to 12 months earlier, the risk of recurrent ischemic cardiovascular events (such as angina, heart attack or stroke) was significantly lower among those who received alirocumab than among those who received placebo. Doses were adjusted to keep LDL levels at 25 to 50 mg per deciliter (mg/dL). About 90% of patients were on high-intensity statins prior to randomization. The mean LDL-C value at baseline was 92.4 mg/dL.
Patients who received Praluent in the trial experienced a 15% reduced risk for major CV events.
- Specifically, in patients receiving high-intensity statin therapy, plus either alirocumab or placebo, the primary end point was a composite of time to death from coronary heart disease, nonfatal myocardial infarction (nonfatal heart attack), fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization.
- After a median follow-up of 2.8 years, the primary end point occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group, a statistically significant effect (p=0.0003). A greater effect was seen in patients with higher LDL (>100 mg/dL) at baseline.
- Secondary end points of death from the individual components of the composite primary endpoint, or all-cause mortality, were not statistically significant.
- Side effects were similar in the two groups, except more local injection-site reactions were seen in the alirocumab group (3.8%) compared to the placebo group (2.1%).
Praluent Side Effects
Praluent (alirocumab) was evaluated in five placebo-controlled trials involving 2,476 patients for the original FDA approval. All patients had HeFH or were otherwise at high risk for heart attack or stroke, and were taking maximally tolerated doses of a statin. Participants taking Praluent had an LDL reduction from 36% to 59% compared to placebo.
The most common side effects (> 5%) have included:
- nasopharyngitis (common cold)
- injection site reactions (erythema/redness, itching, swelling, pain/tenderness)
- influenza (flu-like symptoms).
Allergic reactions (itching, rash, hives) were also reported in 8.6% of patients. Serious allergic reactions, including hypersensitivity vasculitis and hypersensitivity reactions requiring hospitalization, have also been seen.
For a full list of side effects with Praluent, visit here.
Repatha (evolocumab) by Amgen
Repatha (evolocumab) was first FDA-approved in August of 2015.
Repatha injection is used:
- in adults with cardiovascular (heart) disease to reduce the risk of heart attack, stroke, and certain types of heart surgery (coronary revascularization).
- with a cholesterol-lowering diet alone or with diet and other cholesterol-lowering medicines (such as statins or ezetimibe) to treat high blood cholesterol levels known as primary hyperlipidemia, including Heterozygous Familial Hypercholesterolemia (HeFH), to reduce low density lipoprotein (LDL), also known as "bad cholesterol".
- in addition to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) for the treatment of patients with Homozygous Familial Hypercholesterolemia (HoFH) who require additional lowering of LDL-C.
In Phase 3 clinical trials, Repatha lowered LDL by roughly 60% across all study groups in 12-week and 52-week studies. Repatha reduced LDL cholesterol levels by 61% (from a median of 120 mg/dL to 48 mg/dL over 12 weeks). In HoFH, Repatha reduced LDL by 31%.
Cardiovascular Outcomes with Repatha
In December 2017, the FDA approved additional product labeling for Repatha (evolocumab) as the first PCSK9 inhibitor to prevent heart attacks, strokes and coronary revascularizations in adults with established cardiovascular disease.
In the Repatha cardiovascular outcomes study (FOURIER) 27,564 patients who had stable atherosclerotic cardiovascular disease (ASCVD) on statin therapy were evaluated.
Patients who received Repatha had their LCL-C lowered by 59% to a median of 30 mg/dL.
- After a median of 26 months of patient follow-up, Repatha significantly reduced the primary composite endpoint of cardiovascular (heart) death, myocardial infarction (heart attack), stroke, hospitalization for angina (severe chest pain), or revascularization (9.8% of patients in the Repatha group compared to 11.3% of the placebo group).
- The secondary endpoint of time to first occurrence of cardiovascular death, myocardial infarction, or stroke was also significantly reduced from 7.4% to 5.9%.
Repatha significantly reduced the risk of heart attack (27%), stroke (21%), and coronary revascularization (22%).
Side Effects with Repatha
In the OSLER-1 and OSLER-2 open-label studies, side effects occurring with Repatha at a rate of 1% or more included arthralgia or joint pain (4.6%), injection site reactions (4.3%), headache (3.6%), limb pain (3.3%), and fatigue (2.8%).
Neurocognitive effects like confusion were low (under 1%). Repatha treatment was discontinued in 7.2% of 2976 patients. Very low levels of LDL did not appear to affect rates of side effects.
Other side effects include the common cold, upper respiratory tract infections, and injection site reactions. No clinically important drug interactions have been identified with Repatha.
To see a detailed list of side effects visit here.
Repatha: The recommended dose of Repatha (evolocumab):
- 140 mg subcutaneously (under the skin) in the abdomen, thigh, or upper arm every two weeks or 420 mg once monthly for adults with established cardiovascular disease or primary hyperlipidemia (including heterozygous familial hypercholesterolemia).
- For homozygous familial hypercholesterolemia (HoFH), the approved dose is 420 mg subcutaneously once monthly.
Praluent: The initial dose of Praluent (alirocumab):
- 75 mg subcutaneously once every two weeks; most patients will achieve adequate LDL lowering with this dose.
- If preferred, 300 mg once every 4 weeks (monthly) may be given.
- The recommended dose of Praluent in patients with HeFH undergoing LDL apheresis is 150 mg once every 2 weeks. Praluent can be administered without regard to timing of apheresis
Ongoing PCSK9 Inhibitor Questions
Analysts predicted that Repatha and Praluent could each generate annual sales of over $1 billion by 2020, and cardiovascular outcome data that's now available may support this prediction. However, commercial uptake of these drugs has been slow due to insurance payers blocking easy patient access to these costly drugs.
This new drug class adds considerable costs to statin monotherapy -- which today primarily exists in a generic form and is a very affordable option. In fact, a month's supply of generic Lipitor, known as atorvastatin, runs about $8 cash today, using an online coupon. However, PCSK9 inhibitor's are meant to treat the highest-risk patients who cannot reach adequate LDL levels with the maximum allowed doses of statins. Usually, these patients have run out of options.
Questions with PCSK9 inhibitors still remain even with the publication of the outcomes data from the Repatha and Praluent trials:
- What is outcome for the risk of death due specifically to cardiovascular causes, as compared to all-cause death?
- How will the ODYSSEY OUTCOMES trial change clinical practice with respect to targeting very low LDL levels in high-risk patients? How low should we go?
- Will these agents find a place in clinical practice for patients who cannot tolerate statins due to severe muscle symptoms?
- Even with the recent price reduction for Repatha in the U.S., how will the managed care marketplace position this class on their formularies based on cost-effectiveness?
- Will prices go even lower if the 3rd PCSK9 agent inclisiran, in the siRNA class (The Medicines Company) is FDA-approved? And by the way, this agent is dosed only every 6 months.
Investigational siRNA Oligonucelotides
In addition to blocking the PCSK9 receptor to lower LDL, blocking the synthesis of PCSK9 can lower LDL levels. Synthesis of PCSK9 requires mRNA. Phase I and II studies have looked at degradation of the mRNA needed for PCSK9 development with a compound called inclisiran from The Medicines Company (bought by Novartis in 2019).
Inclisiran is an investigational small interfering ribonucleic acid (siRNA) oligonucelotide that inhibits liver synthesis of PCSK9. The study drug may be filed with the FDA for review by the end of 2019.
- In a Phase 3 ORION-9 study report from Sept. 2019, all primary and seconday endpoints were met in a trial of patients with Heterozygous Familial Hypercholesterolemia (HeFH).
- ORION-9 is a 17-month trial in 482 patients with clinical or genetic evidence of HeFH and elevated LDL-C, despite maximum tolerated dose of LDL-C-lowering therapies (e.g., a statin or ezetimibe).
- Inclisiran was given as a 300 mg subcutaneous dose initially, again at three months and then every six months thereafter.
- In Phase I studies, the most common side effects reported were cough, musculoskeletal pain, cold/runny nose, headache, back pain, and diarrhea.
- Unlike Repatha or Praluent which require 12 or 24 injections per year, this new class may only require 2 or 3 shots yearly.
- Further ORION studies to investigate effectiveness, safety and long-term use are ongoing for Atherosclerotic Cardiovascular Disease (ASCVD) or ASCVD-risk equivalents, cardiovascular outcomes, and Homozygous familial hypercholesterolemia (HoFH).
Bococizumab Studies Halted
In November 2016, Pfizer discontinued the global development of bococizumab, their investigational PCSK inhibitor, as well as the two ongoing cardiovascular outcome studies, SPIRE-1 and SPIRE-2.
Pfizer stated that unexpected results occurred in looking at the outcomes of six Phase III studies. Compared to current agents in this class, LDL lowering over time with bococizumab was not as robust, and a higher level of immunogenicity (antidrug antibodies) and a higher rate of injection-site reactions also occurred.
Due to lack of value to shareholders, especially in the currently marketplace, Pfizer decided to halt the studies worldwide.
Lifestyle is Still an Important Adjunct
Everyone should partake in a healthy lifestyle, whether they have high cholesterol or not. We know you've heard this before, but it really is important:
- Quit smoking
- Eat a low fat, low salt diet
- Exercise 30 to 40 minutes a day on most days of the week
- Control your stress, learn to relax
- If you take medications, adhere to your treatment plan and take your medication as directed.
If your cholesterol and LDL levels remains high, even with lifestyle changes, medications to improve your cholesterol might be added to help prevent heart disease and stroke. The statins, PCSK9 inhibitors, and other upcoming investigational agents may offer hope to millions trying to achieve their heart health goals.
Finished: PCSK9 Inhibitors: A New Option in Cholesterol Treatment
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- The Medicines Company Announces Positive Topline Results for ORION-9 Phase 3 Study of Inclisiran in Heterozygous Familial Hypercholesterolemia Patients. Drugs.com. Accessed Dec. 15, 2019 at https://www.drugs.com/clinical_trials/medicines-announces-positive-topline-results-orion-9-phase-3-study-inclisiran-heterozygous-familial-18285.html
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